As an anticancer drug, paclitaxel acts as a microtubule inhibitor in mitosis, and plays an important role in polymerization and stabilization of intracellular microtubule. At the stage of mitosis, paclitaxel disables the separation of microtubules, so that cells are blocked between G2 and M phase. As a result, the fast-dividing tumor cells are arrested at the phase of mitosis by paclitaxel, leading to the death of the cells due to hindered replication. Paclitaxel has important clinical activity to various cancers (for example, breast cancer, ovarian cancer, lung cancer, and bladder cancer, etc.).
Due to poor water-solubility, however, the application of paclitaxel in human body is limited. In order to make paclitaxel suitable for intravenous injection, Bristol-Myers Squibb (BMS) has developed TAXOL®, in which a surfactant polyoxyethylene castor oil (CREMOPHOR® EL) and anhydrous alcohol are added together as co-solvent to enhance the solubility of paclitaxel. Taxol has significant activity to ovarian cancer, breast cancer, lung cancer, esophagus cancer, and head and neck cancer. However, it has been demonstrated that Taxol may induce therapy-related toxicity, and significant acute and accumulative toxicity, such as myelosuppression, febrile neutropenia and hypersensitivity etc. These side effects are related to the surfactant polyoxyethylene castor oil used (Anantbhushan et al., Asia Pac J Clin Oncol. 2013; 9:176-181). Based on clinical research reports and post-marketing safety data, an overall incidence of hypersensitivity induced by Taxol is about 39%. At present, antihistamines and steroids are administrated to patients ahead of time to alleviate the side effects due to the surfactant, when Taxol is used.
In order to improve the water solubility of paclitaxel, structure modifications are also conducted by researchers using functional groups which may provide higher water solubility, for example, sulfonate derivatives (Kingston et al., U.S. Pat. No. 5,059,699 (1991)), and amino-acid ester derivatives (Mathew et al., J. Med. Chem. 35:145-151 (1992)). They exhibit obvious biological activities after modification. However, these modifications may induce undesired side effects or reduce the pharmaceutical efficiency besides the increase of cost of the pharmaceutical formulations.
To avoid adverse effects of CREMOPHOR® EL in paclitaxel formulations, another drug delivery system that does not contain any emulsifying agent or surfactant was developed. Such a system is in the form of micro-particles or nanoparticles and contains albumin, a portion of which forms complexes with paclitaxel. However, this system still has many disadvantages. For example, the formulation requires a large amount of human serum albumin (HSA), which may cause allergy. HSA is still obtained from human blood, and has potential safety risks due to possible contaminations during blood collection and storage. In addition, HSA is relatively expensive and may be in shortage in certain regions.